Use of 4-(2-Flurophenyl)-6-methyl-2-(1-piperazinyl)thieno(2,3-D)-pyrimidine for treating of urinary incontinence

ABSTRACT

4-(2-Fluorophenyl)-6-Methyl-2-(1-Piperazinyl)-Thieno(2,3-D)pyrimidine or a salt thereof is useful for the treatment of urinary incontinence.

This application is a National Stage Application of InternationalApplication Number PCT/GB03/00374, filed Jan. 29, 2003; which claimspriority to Great Britain Application GB 0202265.5, filed Jan. 31, 2002.

FIELD OF THE INVENTION

This invention relates to a new therapeutic use for a known compound.

BACKGROUND OF THE INVENTION

4-(2-Fluorophenyl)-6-methyl-2-(1 -piperazinyl)thieno[2, 3-D]pyrimidinemonohydrate hydrochloride is known (see U.S. Pat. No. 4,695,568) and hasshown activity as an antidepressant. It has serotonin and noradrenergicreuptake blocking properties and this is thought to be the mechanism forits action as an antidepressant. The compound also has 5HT-3 receptorblocking activity.

Urinary incontinence is a distressing condition which is poorly treated.It can be classified as urge (caused by overactive bladder) or stress(for example caused by prolapse of the bladder to a position which putsexcessive pressure on the urethral sphincter). Some unfortunate patientshave both of these types of urinary incontinence which is known asmixed. Other types of urinary incontinence have been described,including functional incontinence, overflow incontinence and transientincontinence (a temporary condition due to infection or medication).Urinary incontinence can be caused by a number of disorders.

All of the drugs used for incontinence have side effect problems whichoften result in non-compliance with treatment or a necessary withdrawalof treatment. Also they are not always effective. For stressincontinence, surgery is often the only answer although anantidepressant that is a serotonin and noradrenaline reuptake blocker,duloxetine, is showing some promise in clinical trials. Otherantidepressants have also shown activity in in vivo models of urinaryincontinence (see U.S. Pat. No. 5,744,474).

SUMMARY OF THE INVENTION

Surprisingly, it has been found that the known compound identified above(referred to herein as MCI-225) has activity in the treatment of urinaryincontinence. Its combination of serotonin and noradrenergic reuptakeblockade and 5HT-3 receptor blockade has not properly been identified asbeing responsible for activity in incontinence. Furthermore MCI-225, atdoses effective in the treatment of urinary incontinence, can produce alower incidence of some of the side-effects which are commonly known tobe associated with the clinical use of selective serotonin reuptakeinhibitors, for example the production of nausea and vomiting or theinduction of sexual dysfunction. It will be appreciated that anysuitable form of the active principle may be used, e.g. another saltform, or a prodrug or active metabolite.

DESCRIPTION OF THE INVENTION

By means of this invention, incontinence can be treated, e.g. controlledor prevented. For this purpose, the active compound can be formulated inany suitable manner together with a conventional diluent or carrier. Theactive compound is preferably administered by the oral route; othersuitable routes of administration include sublingual/buccal,transdermal, intramuscular, intranasal, rectal, parenteral,subcutaneous, pulmonary and topical. The dose of the active agent willdepend on the nature and degree of the complaint, the age and conditionof the patient and other factors known to those skilled in the art. Atypical daily dosage may be 0.1 mg to 1000 mg.

A pharmaceutical composition containing the active ingredient may be inthe form of a sublingual tablet or patch. Suitable compositions for oraluse include tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsions, hard or soft capsules,syrups and elixirs. Suitable additives include sweetening agents,flavouring agents, colouring agents and preserving agents. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients, e.g. inert diluents such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate orsodium phosphate; granulating and disintegrating agents, for examplecorn starch or alginic acid; binding agents, for example starch, gelatinor acacia; and lubricating agents, for example magnesium stearate,stearic acid or talc. The tablets may be uncoated or they may be coatedby known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated, to form osmotic therapeutic tablets for controlled release. Hardgelatin capsules may include an inert solid diluent, for example calciumcarbonate, calcium phosphate or kaolin; soft gelatin capsules mayinclude water or an oil medium, for example peanut oil, liquid paraffinor olive oil.

The data on which this invention is based will now be described. In astudy, using intact animals, the ability of MCI-225 to increase the toneof the urethra/internal sphincter (a desired effect for the treatment ofstress urinary incontinence) was assessed. The results show that MCI-225is able to increase the smooth muscle tone of the lower urinary tractand will thus be of clinical utility in urinary incontinence.

Study

Female Sprague-Dawley rats (225–350 g) were anaesthetised usingurethane. The bladder was exposed through a midline incision into theabdomen and intravesicular pressure was recorded via a catheter insertedinto the bladder. A second catheter was inserted into the bladder toallow infusion of saline using a syringe pump when required. A thirdcatheter was inserted into the bladder and wedged into position in theneck of the bladder with the catheter extending into the urethra. Thisset-up allowed constant infusion of saline into the urethra whilsturethral pressure was recorded. Changes in urethral pressure are assumedto reflect changes in urethral resistance. In each animal,electromyographic (EMG) recordings were made of urethral striated muscleactivity by inserting 2 fine copper electrodes either side of theurethral opening.

Once stable, bladder and urethral pressures were recorded, the bladderwas inflated by direct infusion of physiological saline into the bladderat a rate of 0.046 ml/min. This rate approximates the maximum hourlydiuresis rate. Infusion into the bladder was terminated prior to evokingmicturition and the bladder volume maintained. During and after salineinfusion, simultaneous recordings were made of urethral perfusionpressure and of external sphincter EMG activity. Once these parametershad stabilised, autonomic drive to the lower urinary tract was inhibitedby administration of hexamethonium (10 mg/kg i.v.) and changes tourethral perfusion pressure and external sphincter EMG recorded.Decamethonium (30 mg/kg i.v.) was then added to remove striated muscleactivity. In one group of animals, prior to intravesicular infusion ofsaline a single bolus dose of MCI-225 was administered (3 mg/kg i.v.).In a second group of animals a bolus dose of vehicle was administered.The effect of MCI-225 and vehicle was determined by analysing thechanges in urethral perfusion pressure and external sphincter EMGactivity during and after infusion and following administration of theganglion blocker hexamethonium and then finally decamethonium to blockthe striated muscle activity of the external sphincter.

Results are shown in Tables 1 and 2. They show that MCI-225 caused arise in urethral pressure from 13±1 mmHg to 23±2 mmHg, an increase of77%. The vehicle control on the other hand caused a rise in urethralpressure from 14±1 mmHg to 18±2 mmHg, an increase of only 29%. The risein pressure caused by MCI-225 was statistically significant (p=0.04Students t test) whereas the rise with control was not. This impliesthat the administration of MCI-225 increased the tone of theurethra/internal sphincter, a desired effect for the treatment ofurinary incontinence.

Also of importance are the results seen when hexamethonium wasadministered to the animals. Inhibition of the autonomic nervous systemwith hexamethonium caused a fall in urethral perfusion pressure, and themagnitude of the drop identified the extent to which urethra/internalsphincter tone (due to autonomic nervous system activity) wascontributing to outlet resistance. The drop seen in MCI-225-treatedanimals (55±5%) was greater than vehicle-treated animals (35±7%). Largerfalls in external sphincter activity (EUS-EMG) were seen inMCI-225-treated animals. These results imply that the administration ofMCI-225 had increased the tone of urethra/internal sphincter, thedesired effect for the treatment of stress urinary incontinence.

When decamethonium was administered there were some further smalldecreases in urethral perfusion pressure; decreases from values measuredbefore hexamethonium administration were 64±7% and 44±4% for MCI-225 andvehicle-treated animals respectively.

TABLE 1 Baseline values for mean arterial blood pressure (MAP), heartrate (HR) and urethral perfusion pressure (UP) in anaesthetized femalerats. n MAP (mmHg) HR (beats min⁻¹) UP (mmHg) Control 3 104 ± 3  375 ±12  14 ± 1  MCI-225 3 105 ± 6  405 ± 15  13 ± 2  (3 mg kg⁻¹)

TABLE 2 Values of vesicular pressure (VP) and urethral perfusionpressure (UP) after intravesicular infusion in anaesthetized femalerats. n VP (mmHg) UP (mmHg) Control 3 9 ± 2 18 ± 2  MCI-225 3 8 ± 1 23 ±2  (3 mg kg⁻¹)

1. A method for treating urinary incontinence wherein said methodcomprises administering, to a patient in need of such treatment, aneffective amount of4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-D]pyrimidine ora salt thereof.
 2. The method, according to claim 1, wherein the salt isthe monohydrate hydrochloride.
 3. The method, according to claim 1,wherein the urinary incontinence is stress urinary incontinence.